Mechanism of multidrug resistance to chemotherapy mediated by P-glycoprotein (Review)

Abstract

Multidrug resistance (MDR) seriously limits the clinical application of chemotherapy. A mechanism underlying MDR is the overexpression of efflux transporters associated with chemotherapeutic drugs. P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter, which promotes MDR by pumping out chemotherapeutic drugs and reducing their intracellular concentration. To date, overexpression of P-gp has been detected in various types of chemoresistant cancer and inhibiting P-gp-related MDR has been suggested. The present review summarizes the mechanisms underlying MDR mediated by P-gp in different tumors and evaluated the related signaling pathways, with the aim of improving understanding of the current status of P-gp-mediated chemotherapeutic resistance. This review focuses on the main mechanisms of inhibiting P-gp-mediated MDR, with the aim of providing a reference for the study of reversing P-gp-mediated MDR. The first mechanism involves decreasing the efflux activity of P-gp by altering its conformation or hindering P-gp-chemotherapeutic drug binding. The second inhibitory mechanism involves inhibiting P-gp expression to reduce efflux. The third inhibitory mechanism involves knocking out the ABCB1 gene. Potential strategies that can inhibit P-gp include certain natural products, synthetic compounds and biological techniques. It is important to screen lead compounds or candidate techniques for P-gp inhibition, and to identify inhibitors by targeting the relevant signaling pathways to overcome P-gp-mediated MDR.